Bio-based matrix photocatalysts for photodegradation of antibiotics.

Antibiotics development during the last century permitted unprecedent medical advances. However, it is undeniable that there has been an abuse and misuse of antimicrobials in medicine and cosmetics, food production and food processing, in the last decades. The pay toll for human development and consumism is the emergence of extended antimicrobial resistance and omnipresent contamination of the biosphere. The One Health concept recognizes the interconnection of human, environmental and animal health, being impossible alter one without affecting the others. In this context, antibiotic decontamination from water-sources is of upmost importance, with new and more efficient strategies needed. In this framework, light-driven antibiotic degradation has gained interest in the last few years, strongly relying in semiconductor photocatalysts. To improve the semiconductor properties (i.e., efficiency, recovery, bandgap width, dispersibility, wavelength excitation, etc.), bio-based supporting material as photocatalysts matrices have been thoroughly studied, exploring synergetic effects as operating parameters that could improve the photodegradation of antibiotics. The present work describes some of the most relevant advances of the last 5 years on photodegradation of antibiotics and other antimicrobial molecules. It presents the conjugation of semiconductor photocatalysts to different organic scaffolds (biochar and biopolymers), then to describe hybrid systems based on g-C3N4 and finally addressing the emerging use of organic photocatalysts. These systems were developed for the degradation of several antibiotics and antimicrobials, and tested under different conditions, which are analyzed and thoroughly discussed along the work.

Nonlinear Optical Responses of Photoswitchable Donor-Acceptor Stenhouse Adducts.

This work combines hyper-Rayleigh scattering (HRS) experiments performed in the NIR range (1.30 and 1.60 µm) and quantum chemical calculations to provide a comprehensive description of the second harmonic generation (SHG) responses of donor-acceptor Stenhouse adducts (DASAs). Representative derivatives of the three generations of DASAs, which differ by the nature of their electron-donating and withdrawing moieties and also include clickable species, have been synthesized and their photoswitching behavior fully characterized. The HRS measurements allow us to establish relationships between the magnitude of the SHG response of open forms and the nature of the donor and acceptor groups. The largest SHG responses are obtained for derivatives incorporating either a barbituric acid or an indanedione acceptor unit, while N-methylaniline appears as the most efficient donor group. The calculations support well the experimental data and show that high hyperpolarizabilities are associated to low excitation energies and large extent of the photoinduced intramolecular charge transfer, which enhances the dipole moment variation between the ground and first dipole-allowed electronic excited state. In addition, a complete investigation of the photoswitching kinetics of DASAs in chloroform solution shows important differences, highlighting in particular the role of the donor group on the photoswitching efficiency.

Selective Detection of Choline in Pseudophysiological Medium with a Fluorescent Cage Receptor.

A fluorescent cage receptor for the detection of choline in pseudophysiological medium is described. Not only does this capsule complex choline with an association constant greater than 9.9 × 104 M-1 in buffered medium but it is also selective toward acetylcholine.

Silane-Based SAMs Deposited by Spin Coating as a Versatile Alternative Process to Solution Immersion.

Functionalization of silica surfaces with silane-based self-assembled monolayers (SAMs) is widely used in material sciences to tune surface properties and introduce terminal functional groups enabling subsequent chemical surface reactions and immobilization of (bio)molecules. Here, we report on the synthesis of four organotrimethoxysilanes with various molecular structures and we compare their grafting by spin coating with the one performed by the conventional solution immersion method. Strikingly, this study clearly demonstrates that the spin coating technique is a versatile, fast, and more convenient alternative process to prepare robust, smooth, and homogeneous SAMs with similar properties and quality as those deposited via immersion. SAMs were characterized by PM-IRRAS, AFM, and wettability measurements. SAMs can undergo several chemical surface modifications, and the reactivity of amine-terminated SAM was confirmed by PM-IRRAS and fluorescence measurements.

Optically Sensitive and Magnetically Identifiable Supraparticles as Indicators of Surface Abrasion.

Identifying and ensuring the integrity of products plays an important role in today's globalized world. Miniaturized information taggants in the packaging surface are therefore required to monitor the product itself instead of applying external labels. Ideally, multiple types of information are stored in such additives. In this work, micrometer-sized core-shell particles (supraparticles) were developed to provide material surfaces with both an identifier and a surface abrasion indication functionality. The core of the supraparticles contains iron oxide nanoparticles that allow identification of the surface with a spectral magnetic code resolved by magnetic particle spectroscopy. The fluorescent silica nanoparticles in the supraparticle shell can be abraded by mechanical stress and resolved by fluorescence spectroscopy. This provides information about the mechanical integrity of the system. The application as surfaces, that contain several types of information in one supraparticle, was demonstrated here by incorporating such bifunctional supraparticles as additives in a surface coating.

Modulation of laccase catalysed oxidations at the surface of magnetic nanoparticles.

We explored the coupling of laccases to magnetic nanoparticles (MNPs) with different surface chemical coating. Two laccase variants offering two opposite and precise orientations of the substrate oxidation site were immobilised onto core-shell MNPs presenting either aliphatic aldehyde, aromatic aldehyde or azide functional groups at the particles surface. Oxidation capabilities of the six-resulting laccase-MNP hybrids were compared on ABTS and coniferyl alcohol. Herein, we show that the original interfaces created differ substantially in their reactivities with an amplitude from 1 to > 4 folds depending on the nature of the substrate. Taking enzyme orientation into account in the design of surface modification represents a way to introduce selectivity in laccase catalysed reactions.

Selective recognition of acetylcholine over choline by a fluorescent cage.

A fluorescent hemicryptophane has been synthesized and can be used as a turn on receptor of acetylcholine. A binding constant of 2.4 × 104 M-1 was measured for this neurotransmitter, and its selective and sensitive detection over choline and choline phosphate was achieved. NMR and DFT calculations provide insight into the interactions involved in this selective recognition process.

Structure-based design of human immuno- and constitutive proteasomes inhibitors.

Starting from the X-ray structure of our previous tripeptidic linear mimics of TMC-95A in complex with yeast 20S proteasome, we introduced new structural features to induce a differential inhibition between human constitutive and immunoproteasome 20S particles. Libraries of 24 tripeptidic and 6 dipeptidic derivatives were synthesized. The optimized preparation of 3-hydroxyoxindolyl alanine residues from tryptophan and their incorporation in peptides were described. Several potent inhibitors of human constitutive proteasome and immunoproteasome acting at the nanomolar level (IC50 = 7.1 nM against the chymotrypsin-like activity for the best inhibitor) were obtained. A cytotoxic effect at the submicromolar level was observed against 6 human cancer cell lines.

Why the long hours? Job demands and social exchange dynamics.

BACKGROUND: This study investigates the determinants of long working hours from the perspectives of the demand-control model [Karasek, 1979] and social exchange theory [Blau, 1964; Goulder, 1960]. OBJECTIVE: These two theoretical perspectives are tested to understand why individuals work longer (or shorter) hours. METHODS: The hypotheses are tested with a representative sample of 1,604 employed Canadians. RESULTS: In line with Karasek's model, the results support that high job demands are positively associated with longer work hours. The social exchange perspective would predict a positive association between skill discretion and work hours. This hypothesis was supported for individuals with a higher education degree. Finally, the results support a positive association between active jobs and longer work hours. CONCLUSIONS: Our research suggests that job demands and social exchange dynamics need to be considered together in the explanation of longer (or shorter) work hours.

Cooperative Veratryle and Nitroindoline Cages for Two-Photon Uncaging in the NIR.

Tandem uncaging systems in which a two-photon absorbing module and a cage moiety, linked via a phosphorous clip, that act together by Förster resonance energy transfer (FRET) have been developed. A library of these compounds, using different linkers and cages (7-nitroindolinyl or nitroveratryl) has been synthesized. The investigation of their uncaging and two-photon absorption properties demonstrates the scope and versatility of the engineering strategy towards efficient two-photon cages and reveals surprising cooperative and topological effects. The interactions between the 2PA module and the caging moiety are found to promote cooperative effects on the 2PA response while additional processes that enhance the uncaging efficiency are operative in well-oriented nitroindoline-derived dyads. These synergic effects combine to lead to record two-photon uncaging cross-section values (i.e., up to 20 GM) for uncaging of carboxylic acids.

Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases.

Lysosomal impairment causes lysosomal storage disorders (LSD) and is involved in pathogenesis of neurodegenerative diseases, notably Parkinson disease (PD). Strategies enhancing or restoring lysosomal-mediated degradation thus appear as tantalizing disease-modifying therapeutics. Here we demonstrate that poly(DL-lactide-co-glycolide) (PLGA) acidic nanoparticles (aNP) restore impaired lysosomal function in a series of toxin and genetic cellular models of PD, i.e. ATP13A2-mutant or depleted cells or glucocerebrosidase (GBA)-mutant cells, as well as in a genetic model of lysosomal-related myopathy. We show that PLGA-aNP are transported to the lysosome within 24 h, lower lysosomal pH and rescue chloroquine (CQ)-induced toxicity. Re-acidification of defective lysosomes following PLGA-aNP treatment restores lysosomal function in different pathological contexts. Finally, our results show that PLGA-aNP may be detected after intracerebral injection in neurons and attenuate PD-related neurodegeneration in vivo by mechanisms involving a rescue of compromised lysosomes.

Fluorescent periodic mesoporous organosilica nanoparticles dual-functionalized via click chemistry for two-photon photodynamic therapy in cells.

The synthesis of ethenylene-based periodic mesoporous organosilica nanoparticles for two-photon imaging and photodynamic therapy of breast cancer cells is described. A dedicated two-photon absorbing fluorophore possessing four triethoxysilyl groups and having large two-photon absorption in the near IR region, and azidopropyltriethoxysilane were incorporated into the structure. The mesoporous nanoparticles of 100 nm diameter were further functionalized by means of click chemistry with a propargylated fluorescent bromo-quinoline photosensitizer able to generate singlet oxygen. The photophysical properties and two-photon absorption properties of the nanoparticles were investigated evidencing complementary contribution of the two dyes. Both dyes contribute to the two-photon absorption response of the mesoporous nanoparticles while efficient FRET from the two-photon fluorophore to the quinoline sensitizer is observed. The dual-functionalized nanoparticles were incubated with MCF-7 breast cancer cells. Two-photon confocal imaging demonstrated the endocytosis of the nanoparticles within cancer cells. Moreover, brief two-photon irradiation (3 scans of 1.57 s) at 760 nm at high laser power (3 W) was shown to induce 40% of cancer cell death demonstrating the potential of the dual-functionalized mesoporous organosilica nanoparticles for two-photon photodynamic therapy.

Cooperative dyads for two-photon uncaging.

A series of dyads that combine a photolabile protecting group (PPG) 4,5-dimethoxy-2-nitrobenzyl and different bis-donor or bis-acceptor dissymmetric chromophores acting as two-photon (2P) absorbers were synthesized. Even for low energy transfer efficiency from the 2PA subunit to the uncaging one, improvement of the 2P uncaging sensitivity in the NIR is achieved as compared to isolated PPG. Moreover enhancement of the 2PA response is achieved by tuning the electronic dissymmetry of the 2PA subunit and the arrangement of the complementary subunits in the dyads.

Noncovalent fluorescent probes of human immuno- and constitutive proteasomes.

We report here the synthesis and biological evaluation of fluorescent probes functioning as inhibitors that noncovalently block human immuno- and constitutive proteasomes. These cell-penetrating linear analogues of the natural cyclopeptide TMC-95A were efficient on cells at the nanomolar level and assessed by confocal microscopy and flow cytometry. They may constitute an alternative to previously reported fluorescent probes that all bind covalently to proteasomes.

Tandem triad systems based on FRET for two-photon induced release of glutamate.

Tandem systems allowing enhanced two-photon (2P) absorption in a wavelength range permitting coupling of the primary excitation by energy transfer to an intramolecular cage known to have fragmentation properties suited to photolysis in neuroscience is demonstrated to lead to a 10-fold improvement in the 2P photolysis cross-section at experimentally compatible wavelengths.

Two-photon polarity probes built from octupolar fluorophores: synthesis, structure-properties relationships, and use in cellular imaging.

A series of octupolar fluorophores built from a triphenylamine (TPA) core connected to electron-withdrawing (EW) peripheral groups through conjugated spacers has been synthesized. Their photoluminescence, solvatochromism, and two-photon absorption (2PA) properties were systematically investigated to derive structure-property relationships. All derivatives exhibit two 2PA bands in the 700-1000 nm region: a first band at low energy correlated with a core-to-periphery intramolecular charge transfer that leads to an intense 1PA in the blue-visible range, and a second more intense band at higher energy due to an efficient coupling of the branches through the TPA core. Increasing the strength of the EW end groups or the length of the conjugated spacers and replacing triple-bond linkers with double bonds induces both enhancement and broadening of the 2PA responses, thereby leading to cross-sections up to 2100 GM at peak and higher than 1000 GM over the whole 700-900 nm range. All derivatives exhibit intense photoluminescence (PL) in low- to medium-polarity environments (with quantum yields in the 0.5-0.9 range) and display a strong positive solvatochromic behavior (with Lippert-Mataga specific shifts ranging from 15,000 to 27,500 cm(-1)), triple bonds, and phenyl moieties in the conjugated spacers, thereby leading to larger sensitivities than those of double bonds and thienyl moieties. More hydrophilic derivatives were also shown to be biocompatible, to retain their 2PA and PL properties in biological conditions, and finally to be suitable as polarity sensors for multiphoton cell imaging.

Dimerized linear mimics of a natural cyclopeptide (TMC-95A) are potent noncovalent inhibitors of the eukaryotic 20S proteasome.

Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors used in cancer therapy. Starting from a noncovalent linear mimic of TMC-95A, a series of dimerized inhibitors using polyaminohexanoic acid spacers has been designed and optimized to target simultaneously two of the six active sites of the eukaryotic 20S proteasome. The homodimerized compounds actively inhibited chymotrypsin-like (Ki = 6-11 nM) and trypsin-like activities, whereas postacid activity was poorly modified. The noncovalent binding mode was ascertained by X-ray crystallography of the inhibitors complexed with the yeast 20S proteasome. The inhibition of proteasomal activities in human cells was evaluated. The use of the multivalency inhibitor concept has produced highly efficient and selective noncovalent compounds (no inhibition of calpain and cathepsin) that have potential therapeutic advantages compared to covalent binders such as bortezomib and carfilzomib.

Fluorescence and two-photon absorption of push-pull aryl(bi)thiophenes: structure-property relationships.

Photophysical and TPA properties of series of push-pull aryl(bi)thiophene chromophores bearing electron-donating (D) and electron-withdrawing (A) end-groups of increasing strength are presented. All compounds show an intense intramolecular charge transfer (ICT) absorption band in the visible region. Increasing the D and/or A strength as well as the length of the conjugated path induces bathochromic and hyperchromic shifts of the absorption band as reported for analogous push-pull polyenes. Yet, in contrast with corresponding push-pull polyenes, a significant increase in fluorescence is observed. In particular, chromophores built from a phenyl-bithienyl conjugated path and bearing strong D and A end-groups were found to combine very large one and two-photon brightness as well as strong emission in the red/NIR region. These molecules hold promise as biphotonic fluorescent probes for bioimaging.

Noncovalent inhibition of 20S proteasome by pegylated dimerized inhibitors.

We exploited the concept of polyvalent interactions to produce highly selective and efficient inhibitors of eukaryotic proteasome. This multicatalytic protease with the unique topography of its 6 active sites has emerged as a promising target to treat cancer with the use of the covalent inhibitor bortezomib. We used our reference noncovalent inhibitor, a selective TMC-95A tripeptide linear mimic, to design dimeric noncovalent proteasome inhibitors that target two active sites simultaneously. We synthesized pegylated monomer and dimers of the reference inhibitor and evaluated their capacity to inhibit a mammalian 20S proteasome. The inhibitory power of the dimers depended on the average length of their spacer. Lineweaver-Burk double-reciprocal plots indicated competitive inhibition. The best dimer inhibited CT-L activity 800-times more efficiently than the reference inhibitor.